Mutations in oncogenes and tumor suppressor genes in animal and human tumors may give important clues as to the exposures that led to the tumors. For rodent neoplasms that are pathologically similar to the corresponding human cancer, the rodent disease may be used to model the cellular events involved and to study prevention and therapy. Currently, we are focusing on the K-ras gene in lung cancer. In studies of the role of the oncogene K-ras in genesis of adenocarcinoma of the lung, we are utilizing a mouse model, including tumors induced in vivo, and normal immortalized and transformed alveolar type 2 cells in vitro. We have accumulated considerable evidence that K-ras is actually a tumor suppressor gene in the lung cells which can become adenocarcinoma, including reduced levels of active protein in tumors, and increase in active protein when these cells become growth-arrested. Gene and protein array technologies are being used to identify the key cellular events associated with the functioning of K-ras as a tumor suppressor. Another question is, what is the role of mutant K-ras, found in a high percentage of lung cancers? Several lines of evidence implicate increased reactive oxygen species, including more 8-oxo-dG in DNA, increases in hydrogen peroxide and superoxide, and increases in single-strand breaks in DNA. These findings may lead to new strategies for lung cancer preventon and therapy.